This invention provides a method for treating a subject with glaucoma comprising the steps of administrating a compound or composition which antagonize, inhibits, inactivates, reduce, suppresses, antagonizes, and/or limits the release, synthesis, or production from cells of TNF-xcex1 thereby treating the subject with glaucoma.
The cytokine known as tumor necrosis factor (TNF or TNF-xcex1) is structurally related to lymphotoxin. They have about 40 percent amino acid sequence homology (Old, Nature 330:602-603, 1987). These cytokines are released by macrophages, monocytes and natural killer cells and play a role in inflammatory and immunological events. The two cytokines cause a broad spectrum of effects both in vitro and in vivo, including: (i) vascular thrombosis and tumor necrosis; (ii) inflammation; (iii) activation of macrophages and neutrophils; (iv) leukocytosis; (v) apoptosis; and (vi) shock. TNF has been associated with a variety of disease states including various forms of cancer, arthritis, psoriasis, endotoxic shock, sepsis, autoimmune diseases, infections, obesity, and cachexia. TNF appears to play a role in the three factors contributing to body weight control; intake, expenditure, and storage of energy (Rothwell, Int. J. Obesity 17:S98-S101, 1993).
Histopathologic studies of the glaucomatous optic nerve head in primary open angle glaucoma (POAG) reveal astroglial activation and tissue remodeling, which accompanies neuronal damage. As a part of tissue remodeling, backward bowing and disorganization of the laminar cribriform plates are common characteristics of glaucomatous eyes with either normal or high intraocular pressure.1 These histologic changes are accompanied by the upregulation of extracellular matrix components including collagen and proteoglycan, and adhesion molecules by optic nerve head astrocytes in glaucomatous eyes.2-6 The astroglial activation seen in glaucomatous optic nerve heads likely represents an attempt to limit the extent of the injury and promote the tissue repair process. However, despite the astroglial activation, there is limited deposition of extracellular matrix in glaucomatous optic nerve atrophy, which does not retain characteristics of scar tissue formation.7,8 This suggests that there are diverse cellular responses to the initial event or subsequent tissue injury, which preferentially results in tissue degradation.
In addition, reactive astrocytes following neuronal injury produce various neurotrophic factors and cytokines including TNF-xcex1.14 which play a critical role in the regulation of the synthesis of MMPs.15-17 Furthermore, the release of TNF-xcex1 from its membrane-bound precursor is a MMPs-dependent process.18 Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade components of extracellular matrix. Increased secretion of MMPs by activated glial cells have been implicated in various extracellular matrix remodeling events that occur during normal development and in a number of pathologies including atherosclerosis, arthritis, tumor growth, metastasis and glaucoma.9-13.
TNF-xcex1 is a potent immuno-mediator and pro-inflammatory cytokine that is rapidly upregulated in the brain after injury. It is also known as an inducer of apoptotic cell death via TNF-xcex1 receptor-1 occupancy (Hsu H, Xiong J, Goeddel D V. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell, 1995;81:495-504.).
Open angle glaucoma (OAG) the second leading cause of irreversible blindness in the United States, comprises 2 major syndromes: primary open angle glaucoma (POAG) and normal pressure glaucoma (NPG). POAG is a disease generally characterized by a clinical triad which consists of 1) elevated intraocular pressure (IOP); 2) the appearance of optic atrophy presumably resulting from elevated IOP; and 3) a progressive loss of peripheral visual sensitivity in the early stages of the disease, which may ultimately progress and impair central visual acuity. (Quigley, H A: Open angle glaucoma, New Engl J Med 1993; 328:1097-1106.) Studies have indicated, however, that a surprisingly high percentage of patients with OAG have findings identical to those in POAG but with a singular exception; namely, that the IOP has never been demonstrated to be elevated. Several large population-based studies have documented the high prevalence of this form of glaucoma, often called xe2x80x9clow tension glaucomaxe2x80x9d (but more accurately called xe2x80x9cnormal pressure glaucomaxe2x80x9d) (NPG). The most conservative of these estimates place the percentage of glaucoma that occurs in the presence of xe2x80x9cnormalxe2x80x9d IOP at approximately 20-30% (Sommer A, Intraocular pressure and glaucoma. Am J Ophthalmol 1989;107:186-188, and Sommer A. Doyne Lecture, Glaucoma: Facts and Fancies. Eye 1996;10:295-301.)
In addition to the most common forms of glaucoma described above, there are secondary and closed angle forms of glaucoma which typically result in elevated intraocular pressure due to a variety of mechanisms. In virtually all these other forms of glaucoma, elevated eye pressure is found, and a characteristic optic neuropathy similar to that found in OAG ensues. If untreated, elevated intraocular pressure in these glaucomas invariably leads to visual loss and eventual blindness. In many forms of glaucoma, including those with normal intraocular pressure, lowering of intraocular pressure often fails to halt the progression of the disease. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998 October;126(4):487-97.)
During development and maintenance of the nervous system there exists a complex interdependency between neurons and glial cells. The glial cells maintain normal functioning of the nervous system both by controlling the extracellular environment and by supplying metabolites and growth factors. After damage to the central nervous system, glial cells are thought to support neural growth and metabolism and to scavenge agents toxic to neurons. However, recent evidence challenges the view that glial cells are purely neuroprotective and rather suggests that they could participate in damaging neurons. For example, following focal cerebral ischemia or during the course of neurodegenerative diseases or trauma, reactive astrocytes as well as microglia within the central nervous system produce cytokines, reactive oxygen species and nitric oxide (NO), which are implicated as mediators of tissue injury.
As provided herein, the invention provides a compound or composition containing an agent or molecule which antagonize, inhibits, inactivates, reduce, suppresses, antagonizes, and/or limits the release, synthesis, or production from cells of TNF-xcex1. Such a composition is beneficial for the treatment of glaucoma.
This invention provides a method for treating a subject with glaucoma comprising the steps of administrating a compound agent or composition containing an agent, compound, or molecule, including analogs, isomers, homologues, fragments or variants thereof, which antagonize, inhibits, inactivates, reduce, suppresses, antagonizes, and/or limits the release, synthesis, or production from cells of TNF-xcex1 thereby treating the subject with glaucoma.
In one embodiment, the agent, compound, or molecule suppresses the level or production of TNF-xcex1. In another embodiment, the agent, compound, or molecule inhibits the production of TNF-xcex1.
In another embodiment, the agent, compound, or molecule limits the synthesis or release of TNF-xcex1 from cells. In another embodiment, the compound is thalidomide. In another embodiment, the compound is a selective cytokine inhibitor. In another embodiment, the inhibitor is rolipram or phosphodiesterase 4 inhibitor.
In another embodiment, the agent, compound, or molecule inactivates circulating TNF-xcex1 In another embodiment, the molecule is anti-TNF-xcex1 antibody. In another embodiment, the molecule is infliximab. In another embodiment, the molecule is recombinant TNF-xcex1 soluble receptors. In another embodiment, the molecule is etanercept.
This invention provides a TNF reducer which is hydrazine sulfate, pentoxifylline, ketotifen, tenidap, vesnarinone, cyclosporine, peptide T, sulfasalazine, thorazine, antioxidants, corticosteroids, marijuana, glycyrrhizin, sho-saiko-to, L-carnitine, hyperthermia, or hyperbaric oxygen therapy.
Lastly, this invention provides a method of assaying a subjects serum level of TNF alpha as an indicator for treatment with TNF inhibitors. The assay measures the level of several cytokines in the serum of the subject such as interleukion 10 and interferon gamma.